tbuckley/cabot-search huggingface dataset:
Adaptive RAxML-NG: Accelerating Phylogenetic Inference under Maximum Likelihood using Dataset Difficulty
Authors: Anastasis Togkousidis, Oleksiy M Kozlov, Julia Haag, Dimitri Höhler, Alexandros Stamatakis
Journal: Molecular Biology and Evolution (2023)

Abstract Phylogenetic inferences under the maximum likelihood criterion deploy heuristic tree search strategies to explore the vast search space. Depending on the input dataset, searches from different starting trees might all converge to a single tree topology. Often, though, distinct searches infer multiple topologies with large log-likelihood score differences or yield topologically highly distinct, yet almost equally likely, trees. Recently, Haag et al. introduced an approach to quantify, and implemented machine learning methods to predict, the dataset difficulty with respect to phylogenetic inference. Easy multiple sequence alignments (MSAs) exhibit a single likelihood peak on their likelihood surface, associated with a single tree topology to which most, if not all, independent searches rapidly converge. As difficulty increases, multiple locally optimal likelihood peaks emerge, yet from highly distinct topologies. To make use of this information, we introduce and implement an adaptive tree search heuristic in RAxML-NG, which modifies the thoroughness of the tree search strategy as a function of the predicted difficulty. Our adaptive strategy is based upon three observations. First, on easy datasets, searches converge rapidly and can hence be terminated at an earlier stage. Second, overanalyzing difficult datasets is hopeless, and thus it suffices to quickly infer only one of the numerous almost equally likely topologies to reduce overall execution time. Third, more extensive searches are justified and required on datasets with intermediate difficulty. While the likelihood surface exhibits multiple locally optimal peaks in this case, a small proportion of them is significantly better. Our experimental results for the adaptive heuristic on 9,515 empirical and 5,000 simulated datasets with varying difficulty exhibit substantial speedups, especially on easy and difficult datasets (53% of total MSAs), where we observe average speedups of more than 10×. Further, approximately 94% of the inferred trees using the adaptive strategy are statistically indistinguishable from the trees inferred under the standard strategy (RAxML-NG).
Different airborne particulates trigger distinct immune pathways leading to peanut allergy in a mouse model
Authors: Robert M. Immormino, Johanna M. Smeekens, Priscilla I. Mathai, Katelyn M. Clough, Jackqueline T. Nguyen, Andrew J. Ghio, Donald N. Cook, Michael D. Kulis, Timothy P. Moran
Journal: Allergy (2023)

Abstract Background Environmental exposure to peanut through non‐oral routes is a risk factor for peanut allergy. Early‐life exposure to air pollutants, including particulate matter (PM), is associated with sensitization to foods through unknown mechanisms. We investigated whether PM promotes sensitization to environmental peanut and the development of peanut allergy in a mouse model. Methods C57BL/6J mice were co‐exposed to peanut and either urban particulate matter (UPM) or diesel exhaust particles (DEP) via the airways and assessed for peanut sensitization and development of anaphylaxis following peanut challenge. Peanut‐specific CD4 + T helper (Th) cell responses were characterized by flow cytometry and Th cytokine production. Mice lacking select innate immune signaling genes were used to study mechanisms of PM‐induced peanut allergy. Results Airway co‐exposure to peanut and either UPM‐ or DEP‐induced systemic sensitization to peanut and anaphylaxis following peanut challenge. Exposure to UPM or DEP triggered activation and migration of lung dendritic cells to draining lymph nodes and induction of peanut‐specific CD4 + Th cells. UPM‐ and DEP‐induced distinct Th responses, but both stimulated expansion of T follicular helper (Tfh) cells essential for peanut allergy development. MyD88 signaling was critical for UPM‐ and DEP‐induced peanut allergy, whereas TLR4 signaling was dispensable. DEP‐induced peanut allergy and Tfh‐cell differentiation depended on IL‐1 but not IL‐33 signaling, whereas neither cytokine alone was necessary for UPM‐mediated sensitization. Conclusion Environmental co‐exposure to peanut and PM induces peanut‐specific Tfh cells and peanut allergy in mice.
Characteristics and prognosis of first-time hospitalized patients with generalized pustular psoriasis: insights from national databases
Authors: Jeanette Halskou Haugaard, David Thein, Alexander Egeberg
Journal: British Journal of Dermatology (2023)

In a Danish nationwide population-based study, we found that the mortality rate for patients with first-time hospitalization for generalized pustular psoriasis was zero during hospitalization but increased to 7% within the first 12 months following discharge. The study period spanned 2008–2017; in this period, the most frequently prescribed pharmacotherapy during hospitalization was acitretin, followed by methotrexate.
A promoterless AAV6.2FF-based lung gene editing platform for the correction of surfactant protein B deficiency
Authors: Sylvia P Thomas, Jakob M Domm, Jacob P van Vloten, Liqun Xu, Arul Vadivel, Jacob G E Yates, Yanlong Pei, Joelle Ingrao, Laura P van Lieshout, Sergio R Jackson, Jessica A Minott, Adithya Achuthan, Yeganeh Mehrani, Thomas M McAusland, Wei Zhang, Khalil Karimi, Andrew E Vaughan, Jondavid de Jong, Martin H Kang, Bernard Thebaud, Sarah K Wootton
Journal: Molecular Therapy (2023)

Surfactant protein B (SP-B) deficiency is a rare genetic disease that causes fatal respiratory failure within the first year of life. Currently, the only corrective treatment is lung transplantation. Here, we co-transduced the murine lung with adeno-associated virus 6.2FF (AAV6.2FF) vectors encoding a SaCas9-guide RNA nuclease or donor template to mediate insertion of promoterless reporter genes or the (murine) Sftpb gene in frame with the endogenous surfactant protein C (SP-C) gene, without disrupting SP-C expression. Intranasal administration of 3 × 1011 vg donor template and 1 × 1011 vg nuclease consistently edited approximately 6% of lung epithelial cells. Frequency of gene insertion increased in a dose-dependent manner, reaching 20%-25% editing efficiency with the highest donor template and nuclease doses tested. We next evaluated whether this promoterless gene editing platform could extend survival in the conditional SP-B knockout mouse model. Administration of 1 × 1012 vg SP-B-donor template and 5 × 1011 vg nuclease significantly extended median survival (p = 0.0034) from 5 days in the untreated off doxycycline group to 16 days in the donor AAV and nuclease group, with one gene-edited mouse living 243 days off doxycycline. This AAV6.2FF-based gene editing platform has the potential to correct SP-B deficiency, as well as other disorders of alveolar type II cells.
Transplanted human neural stem cells rescue phenotypes in zQ175 Huntington’s disease mice and innervate the striatum
Authors: Sandra M Holley, Jack C Reidling, Carlos Cepeda, Jie Wu, Ryan G Lim, Alice Lau, Cindy Moore, Ricardo Miramontes, Brian Fury, Iliana Orellana, Michael Neel, Dane Coleal-Bergum, Edwin S Monuki, Gerhard Bauer, Charles K Meshul, Michael S Levine, Leslie M Thompson
Journal: Molecular Therapy (2023)

Huntington's disease (HD), a genetic neurodegenerative disorder, primarily affects the striatum and cortex with progressive loss of medium-sized spiny neurons (MSNs) and pyramidal neurons, disrupting cortico-striatal circuitry. A promising regenerative therapeutic strategy of transplanting human neural stem cells (hNSCs) is challenged by the need for long-term functional integration. We previously described that, with short-term hNSC transplantation into the striatum of HD R6/2 mice, human cells differentiated into electrophysiologically active immature neurons, improving behavior and biochemical deficits. Here, we show that long-term (8 months) implantation of hNSCs into the striatum of HD zQ175 mice ameliorates behavioral deficits, increases brain-derived neurotrophic factor (BDNF) levels, and reduces mutant huntingtin (mHTT) accumulation. Patch clamp recordings, immunohistochemistry, single-nucleus RNA sequencing (RNA-seq), and electron microscopy demonstrate that hNSCs differentiate into diverse neuronal populations, including MSN- and interneuron-like cells, and form connections. Single-nucleus RNA-seq analysis also shows restoration of several mHTT-mediated transcriptional changes of endogenous striatal HD mouse cells. Remarkably, engrafted cells receive synaptic inputs, innervate host neurons, and improve membrane and synaptic properties. Overall, the findings support hNSC transplantation for further evaluation and clinical development for HD.
Genomic architecture of autism spectrum disorder in Qatar: The BARAKA-Qatar Study
Authors: Mona Abdi, Elbay Aliyev, Brett Trost, Muhammad Kohailan, Waleed Aamer, Najeeb Syed, Rulan Shaath, Geethanjali Devadoss Gandhi, Worrawat Engchuan, Jennifer Howe, Bhooma Thiruvahindrapuram, Melissa Geng, Joe Whitney, Amira Syed, Jyothi Lakshmi, Sura Hussein, Najwa Albashir, Amal Hussein, Ilaria Poggiolini, Saba F. Elhag, Sasirekha Palaniswamy, Marios Kambouris, Maria de Fatima Janjua, Mohamed O. El Tahir, Ahsan Nazeer, Durre Shahwar, Muhammad Waqar Azeem, Younes Mokrab, Nazim Abdel Aati, Ammira Akil, Stephen W. Scherer, Madeeha Kamal, Khalid A. Fakhro
Journal: Genome Medicine (2023)

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social and communication skills, restricted interests, and repetitive behaviors. The prevalence of ASD among children in Qatar was recently estimated to be 1.1%, though the genetic architecture underlying ASD both in Qatar and the greater Middle East has been largely unexplored. Here, we describe the first genomic data release from the BARAKA-Qatar Study-a nationwide program building a broadly consented biorepository of individuals with ASD and their families available for sample and data sharing and multi-omics research. In this first release, we present a comprehensive analysis of whole-genome sequencing (WGS) data of the first 100 families (372 individuals), investigating the genetic architecture, including single-nucleotide variants (SNVs), copy number variants (CNVs), tandem repeat expansions (TREs), as well as mitochondrial DNA variants (mtDNA) segregating with ASD in local families. Overall, we identify potentially pathogenic variants in known genes or regions in 27 out of 100 families (27%), of which 11 variants (40.7%) were classified as pathogenic or likely-pathogenic based on American College of Medical Genetics (ACMG) guidelines. Dominant variants, including de novo and inherited, contributed to 15 (55.6%) of these families, consisting of SNVs/indels (66.7%), CNVs (13.3%), TREs (13.3%), and mtDNA variants (6.7%). Moreover, homozygous variants were found in 7 families (25.9%), with a sixfold increase in homozygous burden in consanguineous versus non-consanguineous families (13.6% and 1.8%, respectively). Furthermore, 28 novel ASD candidate genes were identified in 20 families, 23 of which had recurrent hits in MSSNG and SSC cohorts. This study illustrates the value of ASD studies in under-represented populations and the importance of WGS as a comprehensive tool for establishing a molecular diagnosis for families with ASD. Moreover, it uncovers a significant role for recessive variation in ASD architecture in consanguineous settings and provides a unique resource of Middle Eastern genomes for future research to the global ASD community.
Do Pandemics Ever End?
Authors: Joelle M. Abi-Rached, Allan M. Brandt
Journal: New England Journal of Medicine (2023)

Interview with Joelle Abi-Rached on the social, political, economic, and ethical factors that go into a decision to declare that a public health crisis is over. (14:10)Download Since pandemics are sociopolitical as well as epidemiologic events, their end is determined not only by epidemiologic criteria but also by social, political, economic, and ethical concerns.
A statistical deformation model-based data augmentation method for volumetric medical image segmentation
Authors: Wenfeng He, Chulong Zhang, Jingjing Dai, Lin Liu, Tangsheng Wang, Xuan Liu, Yuming Jiang, Na Li, Jing Xiong, Lei Wang, Yaoqin Xie, Xiaokun Liang
Journal: Medical Image Analysis (2023)
Rewarding Site-Based Research
Authors: Matthew G. Dimond, Mona Fiuzat, Robert J. Mentz, Anu Lala-Trindade, David J. Whellan, Mary Norine Walsh, Maria Rosa Costanzo, Amin Yehya, Patrice Desvigne-Nickens, Fady Malik, Christopher M. O’Connor, Michael R. Bristow
Journal: JACC Heart Failure (2023)
Recent insights into eukaryotic double-strand DNA break repair unveiled by single-molecule methods
Authors: Sara De Bragança, Mark S. Dillingham, Fernando Moreno-Herrero
Journal: Trends in Genetics (2023)

Genome integrity and maintenance are essential for the viability of all organisms. A wide variety of DNA damage types have been described, but double-strand breaks (DSBs) stand out as one of the most toxic DNA lesions. Two major pathways account for the repair of DSBs: homologous recombination (HR) and non-homologous end joining (NHEJ). Both pathways involve complex DNA transactions catalyzed by proteins that sequentially or cooperatively work to repair the damage. Single-molecule methods allow visualization of these complex transactions and characterization of the protein:DNA intermediates of DNA repair, ultimately allowing a comprehensive breakdown of the mechanisms underlying each pathway. We review current understanding of the HR and NHEJ responses to DSBs in eukaryotic cells, with a particular emphasis on recent advances through the use of single-molecule techniques.
Horizontally Transferred Salivary Protein Promotes Insect Feeding by Suppressing Ferredoxin-Mediated Plant Defenses
Authors: Yi-Zhe Wang, Yu-Xuan Ye, Jia-Bao Lu, Xin Wang, Hai-Bin Lu, Ze-Long Zhang, Zhuang-Xin Ye, Yu-Wen Lu, Zong-Tao Sun, Jian-Ping Chen, Jun-Min Li, Chuan-Xi Zhang, Hai-Jian Huang
Journal: Molecular Biology and Evolution (2023)

Abstract Herbivorous insects such as whiteflies, planthoppers, and aphids secrete abundant orphan proteins to facilitate feeding. Yet, how these genes are recruited and evolve to mediate plant–insect interaction remains unknown. In this study, we report a horizontal gene transfer (HGT) event from fungi to an ancestor of Aleyrodidae insects approximately 42 to 190 million years ago. BtFTSP1 is a salivary protein that is secreted into host plants during Bemisia tabaci feeding. It targets a defensive ferredoxin 1 in Nicotiana tabacum (NtFD1) and disrupts the NtFD1–NtFD1 interaction in plant cytosol, leading to the degradation of NtFD1 in a ubiquitin-dependent manner. Silencing BtFTSP1 has negative effects on B. tabaci feeding while overexpressing BtFTSP1 in N. tabacum benefits insects and rescues the adverse effect caused by NtFD1 overexpression. The association between BtFTSP1 and NtFD1 is newly evolved after HGT, with the homologous FTSP in its fungal donor failing to interact and destabilize NtFD1. Our study illustrates the important roles of horizontally transferred genes in plant–insect interactions and suggests the potential origin of orphan salivary genes.
Bladder cancer intrinsic LRFN2 drives anticancer immunotherapy resistance by attenuating CD8<sup>+</sup>T cell infiltration and functional transition
Authors: Anze Yu, Jiao Hu, Liangmin Fu, Gaowei Huang, Dingshan Deng, Mingxiao Zhang, Yinghan Wang, Guannan Shu, Lanyu Jing, Huihuang Li, Xu Chen, Taowei Yang, Jinhuan Wei, Zhenhua Chen, Xiongbing Zu, Junhang Luo
Journal: Journal for ImmunoTherapy of Cancer (2023)

Immune checkpoint inhibitor (ICI) therapy improves the survival of patients with advanced bladder cancer (BLCA); however, its overall effectiveness is limited, and many patients still develop immunotherapy resistance. The leucine-rich repeat and fibronectin type-III domain-containing protein (LRFN) family has previously been implicated in regulating brain dysfunction; however, the mechanisms underlying the effect of LRFN2 on the tumor microenvironment (TME) and immunotherapy remain unclear.Here we combined bulk RNA sequencing, single-cell RNA sequencing, ProcartaPlex multiple immunoassays, functional experiments, and TissueFAXS panoramic tissue quantification assays to demonstrate that LRFN2 shapes a non-inflammatory TME in BLCA.First, comprehensive multiomics analysis identified LRFN2 as a novel immunosuppressive target specific to BLCA. We found that tumor-intrinsic LRFN2 inhibited the recruitment and functional transition of CD8+ T cells by reducing the secretion of pro-inflammatory cytokines and chemokines, and this mechanism was verified in vitro and in vivo. LRFN2 restrained antitumor immunity by inhibiting the infiltration, proliferation, and differentiation of CD8+ T cells in vitro. Furthermore, a spatial exclusivity relationship was observed between LRFN2+ tumor cells and CD8+ T cells and cell markers programmed cell death-1 (PD-1) and T cell factor 1 (TCF-1). Preclinically, LRFN2 knockdown significantly enhanced the efficacy of ICI therapy. Clinically, LRFN2 can predict immunotherapy responses in real-world and public immunotherapy cohorts. Our results reveal a new role for LRFN2 in tumor immune evasion by regulating chemokine secretion and inhibiting CD8+ T-cell recruitment and functional transition.Thus, LRFN2 represents a new target that can be combined with ICIs to provide a potential treatment option for BLCA.
A facile, flexible, and multifunctional thermo-chemotherapy system for customized treatment of drug-resistant breast cancer
Authors: Lili Chen, Ahmed Nabil, Nanami Fujisawa, Emiho Oe, Kai Li, Mitsuhiro Ebara
Journal: Journal of Controlled Release (2023)

Anticancer drug resistance invariably emerges and poses a significant barrier to curative therapy for various breast cancers. This results in a lack of satisfactory therapeutic medicine for cancer treatment. Herein, a universal vector system for drug-resistance breast cancer was designed to meet the needs of reversed multidrug resistance, thermo-chemotherapy, and long-term drug release behavior. The vector system comprises polycaprolactone (PCL) nanofiber mesh and magnetic nanoparticles (MNPs). PCL has excellent biocompatibility and electrospinning performance. In this study, MNPs were tailored to be thermogenic in response to an alternating magnetic field (AMF). PCL nanofiber can deliver various chemotherapy drugs, and suitable MNPs encapsulated in the nanofiber can generate hyperthermia and synergistic effect with those chemotherapy drugs. Therefore, a more personalized treatment system can be developed for different breast malignancies. In addition, the PCL nanofiber mesh (NFM) enables sustained release of the drugs for up two months, avoiding the burden on patients caused by repeated administration. Through model drugs doxorubicin (DOX) and chemosensitizers curcumin (CUR), we systematically verified the therapeutic effect of DOX-resistance breast cancer and inhibition of tumor generation in vivo. These findings represent a multifaceted platform of importance for validating strategic reversed MDR in pursuit of promoted thermo-chemotherapeutic outcomes. More importantly, the low cost and excellent safety and efficacy of this nanofiber mesh demonstrate that this can be customized multi-function vector system may be a promising candidate for refractory cancer therapy in clinical.
Value of Invasive Hemodynamic Assessments in Patients Supported by Continuous-Flow Left Ventricular Assist Devices
Authors: Eduard Rodenas-Alesina, Darshan H. Brahmbhatt, Susanna Mak, Heather J. Ross, Adriana Luk, Vivek Rao, Filio Billia
Journal: JACC Heart Failure (2023)
Sequential multimodal therapy in chronic thromboembolic pulmonary hypertension with mixed anatomical lesions: a proof of concept
Authors: Mitja Jevnikar, Sabina Solinas, Philippe Brenot, Benoit Lechartier, Mithum Kularatne, David Montani, Laurent Savale, Carlos Garcia-Alonso, Olivier Sitbon, Antoine Beurnier, Athénaïs Boucly, Sophie Bulifon, Andrei Seferian, Anne Roche, Olaf Mercier, Gérald Simonneau, Elie Fadel, Marc Humbert, Xavier Jaïs
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>This study is a proof of concept highlighting that sequential multimodal therapy combining medical therapy, BPA and PEA may be a safe and effective option in selected CTEPH patients with mixed anatomical lesions and high pre-operative PVR</b>https://bit.ly/3rIBU3D
First‐Aid Hydrogel Wound Dressing with Reliable Hemostatic and Antibacterial Capability for Traumatic Injuries (Adv. Healthcare Mater. 25/2023)
Authors: Junyao Cheng, Hufei Wang, Jianpeng Gao, Xiao Liu, Ming Li, Decheng Wu, Jianheng Liu, Xing Wang, Zheng Wang, Peifu Tang
Journal: Advanced Healthcare Materials (2023)

Wound Dressings In article 2300312, Jianheng Liu, Xing Wang, Zheng Wang, Peifu Tang and co-workers report a multifunctional hydrogel wound dressing developed through mussel-inspired design and zinc oxide-enhanced cohesion which exhibits excellent hemostatic, antimicrobial, and healing-promoting properties. It has great potential in the management of severe hemorrhagic and infected skin wounds.
3D Bioprinting of Neurovascular Tissue Modeling with Collagen‐Based Low‐Viscosity Composites (Adv. Healthcare Mater. 25/2023)
Authors: Sen Wang, Luge Bai, Xiaoxuan Hu, Siqi Yao, Zhiyan Hao, JiaJia Zhou, Xiao Li, Haixia Lu, Jiankang He, Ling Wang, Dichen Li
Journal: Advanced Healthcare Materials (2023)

3D Bioprinting In vitro neurovascular unit (NVU) models are valuable for investigating brain functions and developing drugs. However, it remains challenging to recapitulate the native architectural features and ultra-soft extracellular matrix (ECM) properties. In article 2300004, Ling Wang, Dichen Li, and co-workers propose a novel two-stage bioprinting methodology with collagen-based low-viscosity composites, for functional 3D neurovascular constructs modeling in vitro with low modulus of ECM and high fidelity. The model shows selective barrier properties and distinct expression of critical proteins.
Self‐Aggregated Nanoscale Metal–Organic Framework for Targeted Pulmonary Decorporation of Uranium (Adv. Healthcare Mater. 25/2023)
Authors: Lei Chen, Xiaomei Wang, Mengping Chen, Qiwen Sun, Yemeng Chen, Xiaojie Zhang, Rui Hong, Yigong Xu, Jingwen Guan, Sheng Hong, Dehan Cao, Tingfeng Sun, Ximeng Li, Lanhua Chen, Juan Diwu
Journal: Advanced Healthcare Materials (2023)

Metal–Organic Frameworks The rapid enrichment of ZIF-71-COOH in lungs facilitated by its responsive aggregation in vivo and its selective recognition of uranyl together enable high uranyl removal efficacy from the lungs, highlighting the potential of self-aggregating a nanometal-organic frameworks as a promising drug delivery system for lung targeted uranium decorporation, which is a crucial component in nuclear emergency medical treatment. More details can be found in article 2300510 by Juan Diwu and co-workers.
Smart Nanozymes for Cancer Therapy: The Next Frontier in Oncology (Adv. Healthcare Mater. 25/2023)
Authors: Navya P. N., Sunil Mehla, Amrin Begum, Harit K. Chaturvedi, Ruchika Ojha, Christian Hartinger, Magdalena Plebanski, Suresh K. Bhargava
Journal: Advanced Healthcare Materials (2023)

Smart Nanozymes In article 2300768, Suresh K. Bhargava and co-workers review the potential of smart nanozymes which either exploit the tumor microenvironment or modulate the TME itself for in situ generation of reactive species in effective treatment of cancer. Emphasis is given to tuning of the physico-chemical properties of nanozymes for their use in diagnosis and treatment of cancer.